The long-term goal of this project is to understand how the immune response contributes to COPD. In that[unreadable] context, we submit that the innate immune system of the airways can provide critical signals for host defenses[unreadable] under normal conditions but can also trigger excessive mucous cell metaplasia under other conditions. Indeed,[unreadable] studies of genetically susceptible mice indicate that respiratory paramyxoviruses can trigger a permanent switch[unreadable] to excessive mucous cell metaplasia driven by natural killer T cell (NKT cell) activation and consequent[unreadable] macrophage production of IL-13. Moreover, if mice with an activated NKT cell-macrophage pathway are then[unreadable] exposed to a normally innocuous level of cigarette smoke, they develop a striking increase in small airway mucus[unreadable] production to the point of respiratory death. The nature the response to viral infection or virus-smoke interaction[unreadable] appears to be distinct from the traditional view of NKT cell pressure on macrophages or the development of[unreadable] alternative macrophage activation developed in studies of the response to microbial infection or allergens.[unreadable] However, a similar immune pathway may be active in COPD patients as well as amplification of the terminal ste[unreadable] in the pathway (i.e., mucous cell metaplasia) perhaps by IL-13 production and/or responsiveness in airway[unreadable] epithelial cells. Our new observations prompt us to propose how the immune response may be triggered and[unreadable] maintained to drive the COPD phenotype. We specifically hypothesize that mucous cell metaplasia depends on[unreadable] NKT cell activation and consequent macrophage production of IL-13. This pathway overlaps with the one in[unreadable] allergic asthma, but exhibits distinct features. Furthermore, we suggest that this pathway synergizes with the[unreadable] response to cigarette smoking and thereby produces more severe mucous cell metaplasia and mucus obstruction.[unreadable] We further propose that this disease trait is a critical but treatable feature of COPD and may be associated with[unreadable] distinct biomarkers of bronchitic airway disease versus emphysema or allergic asthma. Accordingly, we have the[unreadable] following specific aims: (1) define the role of the NKT cell-macrophage activation pathway leading to IL-13[unreadable] production and mucous cell metaplasia in COPD patients; (2) define the role of the innate immune program of[unreadable] airway epithelial cells in COPD patients, focusing on auto-amplification of IL-13 action at the level of the[unreadable] epithelium and (3) define the immune mechanism for increased susceptibility to cigarette smoke induction on[unreadable] goblet cell metaplasia and airway hyperreactivity in a mouse model, focusing on the molecular mechanism for[unreadable] NKT cell activation, macrophage activation towards IL-13 production, and epithelial programming towards IL-13[unreadable] and mucin gene expression. Together, the studies aim to establish a new immune pathway that may normally[unreadable] defend against respiratory infection but may be skewed to drive the development of mucous cell metaplasia in[unreadable] COPD.